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Enhanced Therapeutic Efficacy of Cisplatin by Combination with Diethyldithiocarbamate and Hyperthermia in a Mouse Model¹

Cell Biology Laboratory, Departments of Surgery and Medicine [M. S. M., L. N. R.], Division of Medical Oncology, Department of Medicine [J. D. K.], and Department of Surgery [E. F. S.], Evanston Hospital, Evanston, Illinois 60201

A spontaneously metastasizing solid tumor model derived by transplanting the TA3Ha murine mammary carcinoma into the s.c. tail tissue of mice was used to develop a treatment strategy for enhancing the therapeutic efficacy of cisplatin (CDDP). This strategy was based on the findings that diethyldithiocarbamate (DDTC) reduces the toxicity of CDDP, and that localized hyperthermia (HT) augments the antitumor efficacy of CDDP. DDTC (500 mg/kg) reduced the CDDP-induced nephrotoxicity and gastrointestinal toxicity as well as increased the CDDP LD10 from 8 to 20 mg/kg in strain A mice. When CDDP and DDTC were used in multiple treatment schedules at 5-day intervals, DDTC protected the hosts but not the tumors against the toxicity of CDDP. HT administered locally to the tumor 1 h after the injection of CDDP (8 mg/kg) in 1 ml Hanks' balanced salt solution increased the antitumor effect but not the host toxicity. While administration of 8 mg/kg CDDP alone or with HT three times at 5-day intervals caused 100% host mortality, this dose of CDDP could be used with no mortality by combining it with DDTC. A combination of 8 mg/kg CDDP with DDTC (750 mg/kg) and HT (43°C for 60 min), administered three times at 5-day intervals, retarded the local tumor growth significantly compared to the untreated, CDDP plus DDTC and DDTC plus HT control groups of mice. The frequency of lung metastasis in these groups on day 30 of tumor inoculation were 0, 90, 90, and 80%, respectively. The mean survival days of the mice treated with CDDP plus DDTC plus HT was 61 ± 6 compared to 34 ± 5 in the controls. The results presented here demonstrate that by combining CDDP with DDTC, high doses of CDDP can be safely administered. When localized HT is combined with high dose CDDP and DDTC, the tumor growth retardation and the host survival prolongation are significantly better than those obtained with the highest tolerable dose of CDDP alone or CDDP plus HT.

¹ Supported by the Peter Garard Memorial Fund, the Dee and Moody Fund, the Margaret McGrath Memorial Fund, and the American Cancer Society, Illinois Division. This article is dedicated to the memory of Professor Georges Barski, whose pioneering contributions in the field of somatic cell fusion have profoundly influenced modern cancer biology.

² To whom requests for reprints should be addressed, at Cell Biology Laboratory, Departments of Surgery and Medicine, Evanston Hospital, 2650 Ridge Ave., Evanston, IL 60201.

Received 6/26/86. Revised 10/ 9/86. Accepted 10/23/86.